Nucleosides and process

ABSTRACT

Novel 5,6-dihydro-syn(s)-triazine nucleosides and nucleotides and a novel process for preparing the same. The novel nucleosides and nucleotides are disclosed as active in vitro and/or in vivo against susceptible DNA viruses.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation, of application Ser. No. 001,663, filed Jan. 8,1979, now abandoned, which is a continuation of application Ser. No.802,555, filed June 1, 1977, now U.S. Pat. No. 4,171,431 which is acontinuation-in-part of application Ser. No. 715,664, filed Aug. 19,1976, now abandoned.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 3,907,779 issued Sept. 23, 1975 describes and claims thecompound1-(2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneand various derivatives thereof.

U.S. Pat. No. 3,907,779 describes the original discovery,identification, and production of1-(2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneby the controlled fermentation of the microorganism Streptomycesplatensis var. clarensis, NRRL 8035.

The novel compounds of this invention have not been produced by thecontrolled fermentation of the microorganism NRRL 8035, and it is notclear how this objective might be accomplished with the microorganism.

U.S. Pat. No. 3,708,469 issued Jan. 2, 1973 describes the silylationextension of the Hilbert-Johnson reaction for the production of2-thiopyrimidine nucleosides. Winkley and Robins, J. Org. Chem. 35, pp.491-496 (1970) utilized the bis-trimethylsilyl derivative of4-amino-s-triazine-2-(1H)-one for reaction with blocked ribofuranosylhalides.

In this invention, the Hilbert-Johnson reaction is modified to the useof the mono-silylated or disilylated 5,6-dihydro-s-triazines which arenon-aromatic, and an optimal temperature range between minus (-) 25° C.and 25° C. is disclosed. None of the prior art references disclose asilylated non-aromatic sym-triazinone base for reaction with ablocked-pentofuranosyl halide. More specifically, none of the prior artreferences disclose the use of a monosilylated non-aromaticsym-triazinone base for this reaction.

BRIEF SUMMARY OF THE INVENTION

This invention pertains to new organic chemical compounds and a processfor preparing the same. The invention is more particularly directed tonew 1-(2-deoxy-β-D-pentofuranosyl)-5,6-dihydro-s-triazines prepared byreacting a 3',5'-di-O-blocked (e.g. acylated)-2-deoxypentofuranosylhalide with a silylated 5,6-dihydro-s-triazine base. The scope of thisinvention encompasses the 3',5'-blocked nucleosides, the 3'-blockednucleosides, the 5'-blocked nucleosides, and the free nucleosides asprecursors, intermediates, and final products. The correspondingnucleotides are also disclosed.

This invention also comprises an improved process for preparing thecompounds of the invention, as well as a non-microbiological process forpreparing the compound1-(2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with this invention, the 5,6-dihydro-s-triazinenucleosides and nucleotides are represented by structure Ia ##STR1##wherein it is understood that Ia can exist in tautomeric forms such asIb and Ic and that the compounds of this invention are likely to bemixtures of all tautomeric forms, the percentages of each tautomer to beat least partially dependent on the nature of X, R, R', Z, Y and Y', andthe physical environment of the compound ##STR2##

For the purpose of brevity throughout the application and claims, thecompounds will be referred to hereinafter in their tautomeric form,corresponding to structure Ia.

The X substituent is selected from the group consisting of oxygen,imino, lower-alkylimino, and lower-acylimino; R' is selected from thegroup consising of hydrogen and lower-alkyl; Y is selected from thegroup consisting of hydrogen, carboxacyl of from 1 through 18 carbonatoms, and phosphono; Y' is selected from the group consisting ofcarboxacyl and hydrogen; Z is selected from the group consisting ofoxygen and sulfur; R is selected from the group consisting of hydrogen,lower-alkyl, phenyl, benzyl, cyclopropyl, lower-alkoxylower-alkyl, andlower-alkylthiolower-alkyl with the proviso that when R' is hydrogen, Xand Z are oxygen, Y is hydrogen, carboxacyl of from 1 through 18 carbonatoms or phosphono, and Y'-O is in the erythro position, then R ishydrogen, lower alkyl of 2 through 4 carbon atoms, phenyl, benzyl,cyclopropyl, lower-alkoxylower-alkyl, or lower-alkylthiolower-alkyl; andpharmaceutically acceptable salts thereof when X is imino orlower-alkylimino or when Y is phosphono.

The wavy line joining Y'-O to the body of the molecule as shown informula Ia indicates that the Y'-O may be in either the erythro or threoconfiguration.

The term "carboxacyl" as used through the specification and claims meansthe acyl radical of a hydrocarbon carboxylic acid having from 1 to 18carbon atoms, inclusive, or of a hydrocarbon carboxylic acid substitutedwith an inert group. Representative of such carboxacyl groups are thoseof the formula: ##STR3## wherein E is hydrocarbyl of from 1 to 17 carbonatoms, inclusive, or hydrocarbyl of from 1 to 17 carbon atoms,inclusive, wherein a hydrogen atom has been replaced with an inertsubstituent group. Illustrative of acyl radicals of a hydrocarboncarboxylic acid wherein E is hydrocarbyl are the acyl radicals of (a)saturated or unsaturated, straight or branched chain aliphaticcarboxylic acids, for example, acetic, propionic, butyric, isobutyric,tert-butylacetic, valeric, isovaleric, caproic, caprylic, decanoic,dodecanoic, lauric, tridecanoic, myristic, pentadecanoic, palmitic,margaric stearic, acrylic, crotonic, undecylenic, oleic, hexynoic,heptynoic, octynoic acids and the like; (b) saturated or unsaturated,alicyclic carboxylic acids, for example, cyclobutanecarboxylic acid,cyclopentanecarboxylic acid, cyclopentenecarboxylic acid,methylcyclopentenecarboxylic acid, cyclohexanecarboxylic acid,dimethylcyclohexanecarboxylic acid, dipropylcyclohexanecarboxylic acid,and the like; (C) saturated or unsaturated, alicyclic aliphaticcarboxylic acids, for example, cyclopentaneacetic acid,cyclopentanepropionic acid, cyclohexanebutyric acid,methylcyclohexaneacetic acid, and the like; (d) aromatic carboxylicacids, for example, benzoic acid, toluic acid, naphthoic acid,ethylbenzoic acid, isobutylbenzoic acid, 2-methylbutylbenzoic acid, andthe like; and (e) aromatic aliphatic carboxylic acids, for example,phenylacetic acid, phenylpropionic acid, phenylvaleric acid, cinnamicacid, phenylpropionic acid, and naphthylacetic acid, and the like.

The term "hydrocarbon carboxylic acid substituted with an inert group"is used herein to mean a hydrocarbon carboxylic acid wherein one or morehydrogen atoms attached directly to a carbon atom have been replacedwith a group inert to reaction under the conditions hereinafterdescribed for preparing compounds (I) of the invention. Illustrative ofsuch substituent groups are halo-, nitro-, hydroxy-, carboxy-, amino-,cyano-, thiocyanato-, or alkoxy-groups. Illustrative of halo-, nitro-,hydroxy-, carboxy-, amino-, cyano-, thiocyanato- and alkoxy- substitutedhydrocarbon carboxylic acids are mono-, di, and trichloroacetic acid; α-and β- chloropropionic acid; α- and γ-bromobutyric acid; α- and δiodovaleric acid; mevalonic acid; 2- and 4-chlorocyclohexanecarboxylicacid; shikimic acid; 2-nitro-1-methylcyclobutanecarboxylic acid;1,2,3,4,5,6-hexachlorocyclohexanecarboxylic acid;3-bromo-2-methylcyclohexanecarboxylic acid; 4- and5-bromo-2-methylcyclohexanecarboxylic acid; 5- and6-bromo-2-methylcyclohexanecarboxylic acid;2,3-dibromo-2-methylcyclohexanecarboxylic acid;2,5-dibromo-2-methylcyclohexanecarboxylic acid;4,5-dibromo-2-methylcyclohexanecarboxylic acid;5,6-dibromo-2-methylcyclohexanecarboxylic acid;3-bromo-3-methylcyclohexanecarboxylic acid;6-bromo-3-methylcyclohexanecarboxylic acid;1,6-dibromo-3-methylcyclohexanecarboxylic acid;2-bromo-4-methylcyclohexanecarboxylic acid;1,2-dibromo-4-methylcyclohexanecarboxylic acid;3-bromo-2,2,3-trimethylcyclopentanecarboxylic acid;1-bromo-3,5-dimethylcyclohexanecarboxylic acid; homogentisic acid; o-,m-, and p-chlorobenzoic acid; anisic acid; salicylic acid;p-hydroxybenzoic acid; β-resorcylic acid; gallic acid; veratric acid;trimethoxybenzoic acid; trimethoxycinnamic acid; 4,4'-dichlorobenzilicacid; o-, m-, and p-nitrobenzoic acid; cyanoacetic acid; 3,4- and3,5-dinitrobenzoic acids; 2,4,6-trinitrobenzoic acid; thiocyanoaceticacid; cyanopropionic acid; lactic acid; ethoxyformic acid (ethylhydrogen carbonate); butyloxyformic acid; pentyloxyformic acid;hexyloxyformic acid; dodecyloxyformic acid; hexadecyloxyformic acid;malonic acid; succinic acid; glutaric acid and the like.

The term "lower alkyl" is employed in its usual sense as meaning alkylof from 1 to 4 carbon atoms, inclusive, such as methyl, ethyl, propyl,butyl and isomeric forms thereof.

The term "lower-alkoxylower-alkyl" as used throughout the specificationand claims means lower alkyl of from 1 to 4 carbon atoms, inclusive,substituted by alkoxy of 1 to 4 carbon atoms, inclusive.

Illustrative of lower-alkoxylower-alkyl are methoxymethyl, ethoxymethyl,propoxymethyl, 2-ethoxyethyl, 1-ethoxyethyl and the like.

The term "lower-alkylthiolower-alkyl" as used throughout thespecification and claims means lower alkyl of from 1 to 4 carbon atoms,inclusive, substituted by alkylthio of from 1 to 4 carbon atoms.

Illustrative of lower-alkylthiolower-alkyl are methylthiomethyl,ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 1-methylthioethyl,2-ethylthioethyl, 4-methylthiobutyl and the like.

The term "loweracylimino" as used herein means an imine functionsubstituted by an acyl radical of from 1 to 4 carbon atoms, inclusive.

Illustrative of loweracylimino are acetylimino, n-butyroylimino, and thelike.

The term "pharmaceutically acceptable salts" as used throughout thespecification and claims means all pharmaceutically acceptable salts ofthe compounds, including, for example, acid addition salts of compoundsof formula Ia such as hydrochloride, sulfate, acetate and the like, whenX is imino or lower-alkylimino; as well as salts derived from thephosphate function when Y is phosphono, such as sodium, potassium,calcium and ammonium salts thereof. The pharmaceutically acceptablesalts can be used in the same manner as the free base and can beprepared by methods well known in the art.

The free nucleosides of the invention, compounds according to formula Iawherein Y and Y' are hydrogen, are active in vitro against varioussusceptible DNA viruses, for example, susceptible Herpes viruses,including the Herpes simplex type I virus, and thus can be used toinhibit the growth of susceptible DNA viruses in tissue culture mediumat a concentration of from about 25 to about 200 mcg/ml. the freenucleosides of the invention, compounds according to formula Ia whereinY and Y' are hydrogen, can also be used in an in vitro screening systemto determine the presence of susceptible DNA viruses.

The acyl derivatives of the free nucleosides of the invention, compoundsaccording to formula Ia wherein Y and/or Y' are carboxacyl, can be used,advantageously, to upgrade the free nucleosides. This is accomplished byacylating the free nucleosides, recovering the acylated compoundrelatively free of impurities, then deacylating the acylated freenucleoside to give the free nucleoside in a more purified form.

Further, the acyl derivatives of free nucleosides of the invention,compounds according to formula Ia wherein Y and Y' are carboxacyl, canbe used for the same antiviral purposes as the free nucleosides of theinvention.

The 5'-phosphate of the free nucleosides can be used for the samepurposes as the free nucleosides.

In addition, compounds of the formula 2 ##STR4## wherein the Xsubstituent is selected from the group consisting of oxygen, imino,lower-alkylimino, and lower-acylimino; R' is selected from the groupconsisting of hydrogen and lower-alkyl; Y is selected from the groupconsisting of hydrogen, carboxacyl of from 1 through 18 carbon atoms,and phosphono; Y' is selected from the group consisting of carboxacyland hydrogen; Z is selected from the group consisting of oxygen andsulfur; R is selected from the group consisting of hydrogen, methyl,ethyl, n-propyl, isopropyl, phenyl, benzyl, cyclopropyl,lower-alkoxylower-alkyl, and lower-alkylthiolower-alkyl with the provisothat when R' is hydrogen, X and Z are oxygen, Y is hydrogen, carboxacylof from 1 through 18 carbon atoms or phosphono, and Y'-O is in theerythro position, then R is hydrogen, ethyl, n-propyl, isopropyl,phenyl, benzyl, cyclopropyl, lower-alkoxy lower-alkyl, orlower-alkylthiolower-alkyl; and pharmaceutically acceptable saltsthereof when X is imino or lower-alkylimino or when Y is phosphono, canbe used to treat susceptible DNA viral infections in humans and animals,such as those due to susceptible herpes virus. Herpes viruses include,for example herpes simplex type 1, herpes simplex type 2, varicellazoster and cytomegalovirus, as well as equine abortion virus, infectiousbovine rhinotracheitis virus, Marek's disease virus, canine herpes virusand feline rhinotracheitis virus. However, some Herpes viruses such aspseudorabies and equine abortion virus have been tested in vitro against1-(2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneand1-(2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneand, to date, have been demonstrated to be refractory or at best onlyslightly inhibited, i.e. susceptible. To date, treatment of vaginalherpes simplex virus type 2 infection in mice with1-(2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneor1-(2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,given by subcutaneous injection at doses such as those shown in in FIG.1, has resulted in extensions of mean survival times but the number ofmice surviving the infection was not greatly or significantly enhanced.Herpes simplex type 2 virus (HSV-2) has been tested in vitro against1-(2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,1-(2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,1-(2-deoxy-β-D-ribofuranosyl)-5-n-propyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,1-(2-deoxy-β-D-ribofuranosyl)-5-isopropyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,1-(2-deoxy-β-D-ribofuranosyl-5-cyclopropyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,1-(2-deoxy-β-D-ribofuranosyl)-5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneand has been demonstrated to be susceptible. In general, a dose of fromabout 300 mg./kg./day to about 3200 mg./kg./day embraces the effectiverange and can be used for the systemic treatment of susceptible DNAviral infections in humans and animals. More specifically, a dose offrom about 300 mg./kg./day to about 1600 mg./kg./day can be used for thesystemic treatment of infections due to herpes simplex type 1 virus. Thedose can be administered once per day or in increments throughout theday in order that an antiviral concentration of compound is present inthe blood for a minimum of at least 8 hours of the day. For example, arange of about 1×10⁻⁴ M to about 4×10⁻⁴ M of1-(2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dionein the blood can be used to treat infections due to herpes simplex type1 virus. The blood levels can be determined after administration of asuitable radiolabeled form of the compound and determining the level ofthe compound at appropriate times after compound administration. Amethod useful for such determinations is that described by G. L. Neil etal., published in Biochemical Pharmacology, 20, 3295-3308 (1971).

A group of compounds within the scope of formua Ia are those wherein Xand Z are oxygen.

One group of compounds within the scope of formula Ia are those whereinX is imino and Z is oxygen.

Another group of compounds within the scope of formula Ia are thosewherein X is oxygen and Z is sulfur.

One group of compounds within the scope of formula Ia are those offormula Ia-1. ##STR5## wherein R is selected from the group consistingof hydrogen, lower alkyl of 2 through 4 carbon atoms, cyclopropyl; R' isselected from the group consisting of hydrogen and lower alkyl of 1through 4 carbon atoms; Y is selected from the group consisting ofhydrogen, carboxacyl of from 1 through 18 carbon atoms, and phosphono;and Y' is selected from the group consisting of carboxacyl of from 1through 18 carbon atoms and hydrogen.

Another group of compounds within the scope of formula Ia-1 are thosewherein R is selected from the group consisting of hydrogen, ethyl,n-propyl, isopropyl and cyclopropyl.

A group of compounds within the scope of formula Ia-1 are those whereinR' is hydrogen.

A group of compounds wherein the scope of formula Ia-1 are those whereinY and Y' are hydrogen.

A group of compounds within the scope of formula Ia-1 are those whereinY, Y' and R' are hydrogen.

Another group of compounds within the scope of formula Ia-1 are thosewherein Y and Y' are carboxacyl of from 1 through 18 carbon atoms and R'is hydrogen.

Another group of compounds within the scope of formula Ia-1 are thosewherein Y is carboxacyl of from 1 through 18 carbon atoms; Y' and R' ishydrogen.

Still another group of compounds within the scope of formula Ia-1 arethose wherein Y' is carboxacyl of from 1 through 18 carbon atoms; and Yand R' are hydrogen.

A group of compounds within the scope of formula Ia are those of formulaIa-2. ##STR6##

Wherein R is selected from the group consisting of hydrogen, lower alkylof 1 through 4 carbon atoms and cyclopropyl; R' is selected from thegroup consisting of hydrogen and lower alkyl of 1 through 4 carbonatoms; Y is selected from the group consisting of hydrogen, carboxacylof from 1 through 18 carbon atoms, and phosphono; Y' is selected fromthe group consisting of carboxacyl of from 1 through 18 carbon atoms andhydrogen; and pharmaceutically acceptable salts thereof.

A group of compounds within the scope of formula Ia-2 are those whereinR' is hydrogen.

Another group of compounds within the scope of formula Ia-2 are thosewherein Y and Y' are hydrogen.

One group of compounds within the scope of formula Ia-2 are thosewherein Y, Y' and R' are hydrogen.

Another group of compounds within the scope of formula Ia-2 are thosewherein Y and Y' are carboxacyl of from 1 through 18 carbon atoms; andR' is hydrogen.

Another group of compounds within the scope of formula Ia-2 are thosewherein Y is carboxacyl of from 1 through 18 carbon atoms; and Y' and R'are hydrogen.

Still another group of compounds within the scope of formula Ia-2 arethose wherein Y' is carboxacyl of from 1 through 18 carbon atoms; and Yand R' are hydrogen.

Another group of compounds within the scope of formula Ia are those offormula Ia-3 ##STR7## wherein R is selected from the group consisting ofhydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyl; R'is selected from the group consisting of hydrogen and lower alkyl of 1through 4 carbon atoms; Y is selected from the group consisting ofhydrogen, carboxacyl of from 1 through 18 carbon atoms, and phosphono;Y' is selected from the group consisting of carboxacyl of from 1 through18 carbon atoms and hydrogen.

A group of compounds within the scope of formula Ia-3 are those whereinR' is hydrogen.

One group of compounds within the scope of formula Ia-3 are thosewherein Y and Y' are hydrogen.

One group of compounds within the scope of formula Ia-3 are thosewherein Y, Y' and R' are hydrogen.

Another group of compounds within the scope of formula Ia-3 are thosewherein Y and Y' are carboxacyl of from 1 through 18 carbon atoms and R'is hydrogen.

Another group of compounds within the scope of formula Ia-3 are thosewherein Y is carboxacyl of from 1 through 18 carbon atoms, Y' and R' arehydrogen.

Still another group of compounds within the scope of formula Ia-3 arethose wherein Y' is carboxacyl of from 1 through 18 carbon atoms, Y andR' are hydrogen.

Another group of compounds within the scope of formula Ia are those offormula Ia-4. ##STR8## wherein R' is selected from the group consistingof hydrogen and lower alkyl of 1 through 4 carbon atoms; Y is selectedfrom the group consisting of hydrogen, carboxacyl of from 1 through 18carbon atoms, and phosphono; and Y' is selected from the groupconsisting of carboxacyl of from 1 through 18 carbon atoms and hydrogen.

A group of compounds within the scope of formula Ia-4 are those whereinR' is hydrogen.

One group of compounds within the scope of formula Ia-4 are thosewherein Y and Y' are hydrogen.

Another group of compounds within the scope of formula Ia-4 are thosewherein Y, Y' and R' are hydrogen.

Another group of compounds within the scope of formula Ia-4 are thosewherein Y and Y' are carboxacyl of from 1 through 18 carbon atoms and R'is hydrogen.

Another group of compounds within the scope of formula Ia-4 are thosewherein Y is carboxacyl of from 1 through 18 carbon atoms; and Y' and R'are hydrogen.

Still another group of compounds within the scope of formula Ia-4 arethose wherein Y' is carboxacyl of from 1 through 18 carbon atoms; Y andR' are hydrogen.

For reason of brevity, compounds wherein Y'-O is in the threoconfiguration are not rendered in the same manner as compounds withinthe scope of formula Ia-1, Ia-2, Ia-3 and Ia-4, but the sameillustrative scoping is intended.

In accordance with the process of this invention5,6-dihydro-5R-6R'-s-triazines of the formula: ##STR9## wherein R isselected from the group consisting of hydrogen, lower alkyl, phenyl,benzyl, cyclopropyl, lower-alkoxylower-alkyl andlower-alkylthiolower-alkyl; R' is selected from the group consisting ofhydrogen and lower alkyl; X is selected from the group consisting ofoxygen, imino, lower-alkylimino and lower-acylimino; and Z is selectedfrom the group consisting of oxygen and sulfur; are mono- or disilylatedby reaction with a trialkylsilyl halide, a trialkylsilylacetamide, atrimethylsilylamine, or hexamethyldisilazane, to form the correspondingmono-silyl compounds of formula A or the corresponding di-silylcompounds of formula B, respectively: ##STR10## wherein R, R', X and Zhave the above indicated meanings, and A₁, A₂, and A₃ represent loweralkyl groups of 1 to 4 carbon atoms.

A novel step of the process described, comprises reacting a mono-silylcompound of formula A with a 2-deoxy-3,5-blocked-D-pentofuranosyl halidein the presence of a Lewis acid at an initial temperature of about minus(-) 25° C., with subsequent warming to about 25° C.

A disilyl compound of formula B can also be reacted with a2-deoxy-3,5-blocked-D-pentofuranosyl halide in the presence of a Lewisacid at an initial temperature of about minus (-) 25° C. with subsequentwarming to about 25° C. When the trialkylsilyl halide is used, an acidacceptor of the kind already indicated is included in the reactionmixture comprising a suitable reaction medium as is known in the art;see Silylation of Organic Compounds, Pierce Chemical Co., Rockford, Ill.(1968) and Chem. Pharm. Bull. 12 p. 352 (1964). In the practice of thisinvention, pyridine was successfully employed. The silylated5,6-dihyro-s-triazine bases are recovered for further reaction with theblocked pentofuranosyl halides by conventional methods as described bythe examples herein.

The sugar and the silylated based are reacted in the presence of a Lewisacid such as stannic halide, e.g., stannic chloride or bromide, and asolvent medium such as benzene, ethylene dichloride, toluene,chloroform, acetonitrile (preferred), nitromethane, dioxane andtetrahydrofuran. Mercuric bromide (preferably mixed with an equal weightof a molecular sieve, Linde Type 3A or 4A) or silver perchlorate canalso be used as catalyst. The initial reaction is effected attemperatures around minus (-) 25° C. Later, the reaction temperature isincreased to about 25° C. as described.

The "blocked" 2-deoxypentofuranosyl halide reactants include especiallythe bromo- and chloro-halides with blocking groups, i.e., a carboxacylprotective group as commonly used in sugar chemistry. Ordinarily, theblocking groups will be acetyl, toluoyl or benzoyl, but can be anyequivalent protective carboxacyl group. The method of preparing theblocked sugar halide reactants is conventional, e.g., reacting the sugarwith an alcohol in the presence of acid, protecting the free OH-groupswith a suitable blocking group and forming the sugar halide by treatmentwith anhydrous, hydrogen halide in an organic solvent. The function ofthe blocking group is to protect the hydroxyl groups during thereaction.

Illustrative sugar halides are1-(2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl)-chloride and1-(2-deoxy-3,5-di-O-toluoyl-D-xylofuranosyl)-chloride.

The intermediate1-(2-deoxy-3,5-di-O-acyl-β-D-ribofuranosyl)-5,6-dihydro-5R-6R'-s-triazinesare recovered by conventional techniques such as solvent extraction,precipitation, filtration, crystallization and chromatography. Theblocking groups are removed as described in order to obtain the objectcompounds1-(2-deoxy-β-D-pentofuranosyl)-5,6-dihydro-5(R)-6R'-s-triazines.

The free nucleosides of the invention, compounds according to formula Iawherein Y and Y' are hydrogen, can be acylated by standard proceduresutilizing an acid halide or anhydride of an appropriate carboxylic acidincluding, for example, acetic anhydride, acetyl chloride, palmitylchloride, benzoyl chloride and succinic anhydride.

Various acylates of the free nucleosides of the invention can be made,and these acylates are useful to upgrade the free nucleosides. Byfollowing the procedure of Example 1, Part B, the 3',5'-di-esters areformed.

The 5'-mono-esters can be formed by standard procedures using a minimumamount of acylating agent, see, e.g. Example 6, Part B.

The 3'-mono-esters can be formed by tritylating the free nucleoside togive the 5'-trityl derivative, acylating with the acid halide oranhydride of the appropriate carboxylic acid such as disclosed in U.S.Pat. No. 3,426,012, Columns 5 and 6, to give the 3'-mono-ester 5'-tritylderivative, which then can be converted to the 3'-mono-ester by removalof the trityl group.

Phosphorylation is readily accomplished by the method described by D.Mitsunoku, K. Kato, and J. Kimura in Jour. Am. Chem. Soc. 91, p. 6510(1969). After removal of the 3'-O-acyl group there are obtained5'-phosphates according to the invention that have the desiredanti-viral activity.

A preferred method of acylating the 3'-position is to first form anether at the 5'-position with tert-butyldimethylsilyl chloride asdescribed in Example 6, Part A. Acylation at the 3'-position is thenaccomplished as described in Example 6, Part B to obtain, e.g.,1-(5-O-tert-butyldimethylsilyl-3-O-lauroyl-2-deoxy-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4(1H,3H)-dionewhich is desilylated with tetra-n-butyl ammonium fluoride intetrahydrofuran as in Example 6, Part C.

Preparation 1 Synthesis of new precursor5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione Part A: Ethylbiuret

To a quantity [1.0 kg. (7.56 mole)] of ethyl allophanate is added 2.3liter of 70 percent aqueous ethylamine. The reaction vessel is flushedwith nitrogen gas in order to remove the oxygen present, and thereaction mixture is heated at temperatures in the range of 35° to 49° C.for 23 hours. The solution obtained is concentrated by removing much ofthe water and excess ethylamine by evaporation under reduced pressureand 45° C. A slurry results, which is cooled to 5° C. and filtered. Thefilter cake obtained is washed with 200 ml. of ice-cold, absoluteethanol. The washed crystals are dried under reduced pressure at 60° C.to give 802 gm. of ethylbiuret and starting ethyl allophanate. The 802gm. quantity is again reacted with 2250 ml. of the 70 percent aqueousethylamine diluted with an equal volume of water (2250 ml.). Thisreaction mixture is heated with stirring at 60° C. for 18 hours under anitrogen atmosphere, and again much of the water and ethylamine isremoved by evaporation under reduced pressure. The final volume is 1800ml. The slurry thus obtained is cooled to 5° C. and filtered. Afterwashing the white filter cake with ice-water and drying under reducedpressure at 50° C., there is obtained 597 gm. (62.69 percent yield) ofthe desired ethylbiuret having a melting point of 158.5° to 160° C.

Part B: 1-Ethyl-5-azauracil

The ethylbiuret prepared in Part A, above, [592 gm. 4.7 mole] isdispersed in 24 liter absolute ethanol and 1.6 liter benzene. Thisreaction mixture is heated to the reflux temperature and 3.5 liter ofsolvent medium is removed by distillation. The solution is cooled to 60°C. and 2090 gm. of a 25 percent solution of sodium methoxide in methanolis slowly added over an interval of five minutes. That addition isfollowed by the addition of 820 gm. of ethylformate. This reactionmixture is heated at the reflux temperature for three (3) hours,whereupon the solution is cooled to 38° C. and concentrated hydrochloricacid is added slowly until the pH of the solution is 2. To the acidifiedsolution is added more (3.4 liter) benzene. Then 2 liter of the solventmedium is removed by distillation under reduced pressure and 50° C. Themixture is then heated to 75° C. and filtered in order to remove thesodium chloride produced by the reaction. The filter cake of salt iswashed with hot absolute ethanol which washings are added to thefiltrate. The volume of the combined filtrate and absolute ethanolwashings is reduced to 5 liter by evaporation under reduced pressure at50° C. The resulting concentrate is cooled at 5° C. for 18 hours whilecrystals form. The crystals are collected on a filter and washed withcold (5°) ethanol. The washed crystals are dried in an oven underreduced pressure at 50° C. for 18 hours. There is thus obtained 408 gm.of crude product having a melting point at 137° to 139° C. A furtherpurification is achieved by dissolving the 408 gm. in 4 liter methanolat reflux temperature. This solution is concentrated by allowing themethanol to evaporate to a volume of 2 l. while being heated on a steambath. The concentrated solution is allowed to cool slowly to 25° C. Itis then chilled to 5° C. for two hours. The crystals that form arecollected on a filter and the filter cake is washed with ice-coldmethanol. After drying there is obtained 389 gm. (58.7 percent yield) of1-ethyl-5-azauracil having a melting point of 141° to 142° C. A secondcrop of crystals is recovered from the mother liquor after furtherconcentration and cooling.

An analytical sample is prepared by recrystallizing fromtetrahydrofuran. A 1.0 gm. sample is dissolved in 50 ml. and filteredwhile hot. The filtrate is concentrated to a volume of 25 ml. byevaporation of solvent medium and 50 ml. toluene is added. This solutionis again concentrated to a volume of 25 ml. by evaporating the solventson a steam bath. This concentrate is cooled to 25° C. and crystalsformed. The crystals are collected on a filter, the filter cake isrinsed with Skellysolve B®, essentially n-hexane, B.P. 60° C.-68° C.,Skellysolve Oil Co., Inc. After drying the crystals in air, there areobtained 0.8 gm. of pure 1-ethyl-5-azauracil having a melting point of144° C. to 145° C.

Analysis: Calc'd for C₅ H₇ N₃ O₂ : C, 42.55; H, 5.00; N, 29.78. Found:C, 42.33; H, 5.08; N, 29.36.

Part C: The desired precursor,5-Ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione

To a quantity [370 gm., 2.62 mole] of the 1-ethyl-5-azauracil preparedin Part B, above is added 2200 ml. water and 40 gm. of 5 percent rhodiumon activated charcoal. This mixture is put in a Parr hydrogenationchamber and hydrogen gas is introduced to a pressure of 50 pounds persquare inch (p.s.i.) and the reaction system is heated to 100° C. Whenuptake of hydrogen ceases, the hydrogen pressure is increased to 200p.s.i. and held there for 18 hours. The hydrogenated reaction mixture isrinsed out of the reaction chamber with hot water, filtered while hot,and the filter is washed with one liter of water at 80° C. The aqueoussolution is set aside at 25° C. for 18 hours, during which intervalcrystals form. The crystals are collected on a filter and dried at 50°C. under reduced pressure. There is thus obtained 70 gm. of5-ethyl-5,6-dihydro-s-triazine-2,4-(1H, 3H)-dione having a melting rangebetween 220° C. and 224° C.

The mother liquor is concentrated by evaporating water until a slurry isobtained and the volume is 500 ml. After cooling, the crystals arecollected on a filter and dried at 70° C. under reduced pressure. Thereis thus obtained 159 gm. of a second crop. These crystals are dissolvedin 4.5 liter of methanol which has been heated to boiling. Thismethanolic solution is chilled to 5° C., set aside for 18 hours at thattemperature, and then filtered. The filter cake is washed with 300 ml.of ice-cold methanol and dried at 50° C. under reduced pressure. Thereis thus obtained 77 gm. of product having a melting range between 220°C. and 224° C.

The filtrate is concentrated to a one liter volume by evaporatingmethanol. There is thus obtained 15.46 gm. of product which has amelting range between 211° C. and 218° C. After combining the 70 gm., 77gm., and 15 gm. crops by dissolving them in 4 liter of boiling methanol,there is obtained, after chilling, an analytical sample weighing 138 gm.which has a melting range between 221° C. and 225° C.

Analysis: Calc'd for C₅ H₉ N₃ O₂ : C, 41.95; H, 6.34; N, 29.36. Found:C, 41.89; H, 6.55; N, 29.31.

Preparation 2 Synthesis of known precursor5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione Part A: Methylbiuret

A reaction mixture consisting of 200 gm. (1.5 mole) ethyl allophanateand 800 ml. of 40 percent aqueous methylamine is introduced into a twoliter flask and the flask is loosely stoppered. After stirring for from3 to 5 hours a clear solution is obtained. Stirring is continued for atotal of 18 hours. The reaction medium is then allowed to evaporateuntil the odor of methylamine is no longer noticeable. The aqueousslurry thus obtained is filtered and the aqueous filtrate is discarded.The white solid on the filter is recrystallized from ethanol whichcontained a small proportion of methanol. There is thus obtained 125 gm.(71 percent yield) of methylbiuret as white crystals having a meltingpoint of 173° C. to 175° C.

Part B: 1-methyl-5-azauracil

A reaction mixture consisting of 70.2 gm. (0.6 mole) of the1-methylbiuret prepared in Part A above, 3.5 liter absolute ethanol, and200 ml. benzene is heated to the reflux temperature with stirring in a5-liter, three-necked flask fitted with a reflux condenser, a stirrer,and thermometer. The top of the condenser is fitted with a nitrogenoutlet, but no water is run through the condenser. After removing thenitrogen outlet, 200 ml. of the medium is allowed to distill through thecondenser. The reaction mixture is then cooled to 60° C., before 28 gm.(1.2 mole) of sodium metal is added slowly over an interval of five (5)minutes. A white solid precipitates, but stirring is continued until allthe sodium is dissolved. At this point, 104 gm. (1.4 mole) of ethylformate is added in one portion and the reaction mixture is again heatedto the reflux temperature (about 75° C.) and refluxed for three (3)hours. The reaction mixture is cooled to about 30° C. and hydrogenchloride gas is blown over the surface until an acid pH is attained. Thereaction mixture is again heated at the reflux temperature for 15minutes. The hot mixture is filtered through a diatomaceous earth filterand the filter is washed with hot ethanol. The filtrate and washings areconcentrated to a volume of 200 to 300 ml. by removing medium byevaporation under reduced pressure. The concentrate is cooled to 5° C.and set aside at that temperature for several hours for crystallization.The crystals are collected on a filter and washed with cold ethanol.After drying the crystals under reduced pressure there is obtained 69gm. (90% yield) of 1-methyl-5-azauracil having a melting range from 200°C. to 205° C. A sample recrystallized three times from ethanol has amelting point of 213° C. to 214° C.

Part C: The desired known precursor,5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione

A hydrogenation mixture consisting of 203.5 gm. (1.6 moles) of the1-methyl-5-azauracil prepared in Part B, above, 7 teaspoons of RaneyNickel, and 8 liter ethanol in a five-gallon autoclave is subjected to750 p.s.i. hydrogen pressure at 125° C. for an interval of 12 hours. Thehydrogen is flushed out of the chamber with nitrogen gas and thereaction mixture is siphoned out of the chamber into a five-galloncarboy. The walls of the chamber are washed down with water and thesewashings are siphoned into the carboy. The carboy is then flushed withnitrogen (<20 p.s.i.) so as to force the medium through a filter stickonto a filter bed of Dicalite 4200 (diatomaceous earth). The solids areretained in the carboy substantially undisturbed. The medium is thensucked through the dicalite filter under reduced pressure until 1 inchof liquid remains. The solids retained in the bottom of the carboy arenow mixed with two (2) liters water and 500 ml. Dicalite 4200 and thismixture is added to the filter cake. The filter cake is then washed withwater. The filtrate and washings are combined and the water is removedto a volume of 1200 ml. by evaporation under reduced pressure, 20 mmmercury, and 50° C. temperature. The concentrate thus obtained is heatedto 90° C., and 95% aqueous ethanol is added to a volume of two liters.Upon cooling, crystallization occurs. The crystals are collected on afilter and dried. There is thus obtained 120 gm. (59% yield) of5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione having a melting pointof 252° C. to 254° C.

Preparation 3 Synthesis of new precursor5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione Part A: n-Butylbiuret

Following the procedure described in Preparation 2, Part A, above, butsubstituting n-butylamine for the methylamine, there is prepared 60 gm.(35% yield) of n-butylbiuret having a melting point of 129° to 131° C.

Analysis: Calc'd for C₆ H₁₃ N₃ O₂ : C, 45.27; H, 8.23; N, 26.40. Found:C, 45.27; H, 8.02; N, 26.48.

Part B: 1-n-Butyl-5-azauracil

Following the procedure described in Preparation 2, Part B, above, butsubstituting the n-butylbiuret prepared in Part A, above, for themethylbiuret, there is prepared 60 gm. (92% yield) of1-n-butyl-5-azauracil.

Part C: The desired new precursor,5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione

Following the procedure described in Preparation 2, Part C, above, butsubstituting the 1-n-butyl-5-azauracil prepared in Part B, above, forthe 1-methyl-5-azauracil, there is prepared 40 gm. (67% yield) of thedesired new precursor 5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dionehaving a melting point of 205° C. to 207° C.

Analysis: Calc'd. for C₇ H₁₃ N₃ O₂ : C, 49.12; H, 7.65; N, 24.55. Found:C, 49.17; H, 7.68; N, 24.56.

Preparation 4 Synthesis of new precursor,3,4,5,6-tetrahydro-4-imino-5-methyl-s-triazine-2-(1H)-one Part A: Newantecedent, 5,6-dihydro-5-methyl-4-thio-s-triazine-2-(1H,3H)-one

12.90 gm. of 5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3)-dione (preparedas in Preparation 2, Part C, above) is added to 500 ml. of pyridine.With protection from moisture, 33.0 ml. ofBistrimethylsilyltrifluoroacetamide is added and the reaction mixture isstirred at 25° C. for 18 hours. This reaction mixture is poured into7.50 gm. phosphorus pentasulfide from which pyridine has been distilled(under vacuum) twice; heated at reflux, with stirring, for 42 hours.After first cooling to 25° C., the residue is evaporated under vacuum todryness and tritrated with chloroform and the resulting solids washedwith chloroform to yield 9.45 gm. of5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione. The chloroformsolution is evaporated to dryness and the resulting residuechromatographed on 1.4 kg. silica gel using 2% methanol in chloroform aseluent. Fractions are collected with rf. 0.7 (in 15%methanol/chloroform) to give 395 mg. of5,6-dihydro-5-methyl-2-thio-s-triazine-2,4-( 1H,3H)-dione and thosefractions containing material with rf. 0.65 (15% methanol/chloroform) toyield 92 mg. of5,6-dihydro-5-methyl-4-thio-s-triazine-2,4-(1H,3H)-dione, melting point273°-274° C.

Analysis: Calc'd. for C₄ N₇ N₃ OS: (145.18): C, 33.09; H, 4.86; N,28.94; S, 22.08. Found: C, 33.01; H, 5.20; N, 29.18; S, 21.67.

Following the same procedure, but substituting

5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

5,6-dihydro-5-ethyl-s-triazine-2,4-(1H,3H)-dione,

5,6-dihydro-5-n-propyl-s-triazine-2,4-(1H,3H)-dione,

5,6-dihydro-5-cyclopropyl-s-triazine-2,4-(1H,3H)-dione,

5,6-dihydro-5-isopropyl-s-triazine-2,4-(1H,3H)-dione,

5,6-dihydro-5-methoxymethyl-s-triazine-2,4-(1H,3H)-dione, and

5,6-dihydro-5-methylthiomethyl-s-triazine-2,4-(1H,3H)-dione for the5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione there are prepared thecorresponding

5,6-dihydro-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-ethyl-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-n-propyl-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-cyclopropyl-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-isopropyl-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-methoxymethyl-4-thio-s-triazine-2-(1H,3H)-one, and

5,6-dihydro-5-methylthiomethyl-4-thio-s-triazine-2-(1H,3H)-one,respectively.

Part B: New precursor,3,4,5,6-tetrahydro-4-imino-5-methyl-s-triazine-2-(1H)-one

A cold reaction mixture is prepared by mixing 0.725 gm. (0.005 mole) ofthe 5,6-dihydro-5-methyl-4-thio-s-triazine-2-(1H,3H)-one prepared as inPart A, above, and 25 ml. of a saturated methanolic solution of ammoniawhich has been cooled to 0° C. The reaction mixture is put in astainless steel pressure chamber and heated at 105° C. for 72 hours.After cooling and filtering, the filter cake is washed with ice-coldmethanol and dried under reduced pressure at 50° C. and the productcollected. The filtrate and methanol washings are combined and themethanol is removed by evaporation. The residue thus obtained istriturated with 5 ml. methanol at 25° C. to give additional product.Both crops of product are combined and dissolved in 20 ml. of boilingethanol, water being added until solution is complete. The aqueousethanol solution is then cooled to 5° C. and refrigerated at thattemperature for 18 hours. The crystals that are formed are collected ona filter and washed with cold ethanol at 5° C. The washed crystals aredried under reduced pressure at 50° C. to give3,4,5,6-tetrahydro-4-imino-5-methyl-s-triazine-2-(1H)-one.

Following the procedure of Preparation 4, Part B, but substituting

5,6-dihydro-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-ethyl-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-n-propyl-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-cyclopropyl-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-isopropyl-4-thio-s-triazine-2-(1H,3H)-one,

5,6-dihydro-5-methoxymethyl-4-thio-s-triazine-2-(1H,3H)-one, and

5,6-dihydro-5-methylthiomethyl-4-thio-s-triazine-2-(1H,3H)-one for the5,6-dihydro-5-methyl-4-thio-s-triazine-2-(1H,3H)-one, there are preparedthe corresponding

3,4,5,6-tetrahydro-4-imino-s-triazine-2-(1H)-one,

3,4,5,6-tetrahydro-4-imino-5-ethyl-s-triazine-2-(1H)-one,

3,4,5,6-tetrahydro-4-imino-5-n-propyl-s-triazine-2-(1H)-one,

3,4,5,6-tetrahydro-4-imino-5-cyclopropyl-s-triazine-2-(1H)-one,

3,4,5,6-tetrahydro-5-isopropyl-4-imino-s-triazine-2-(1H)-one,

3,4,5,6-tetrahydro-5-methoxymethyl-4-imino-s-triazine-2-(1H)-one, and

3,4,5,6-tetrahydro-5-methylthiomethyl-4-imino-s-triazine-s-(1H)-one,respectively.

Preparation 5 Preparation of4-imino-4-N-acetyl-3,4,5,6-tetrahydro-5-methyl-s-triazine-2-(1H)-one

To 1.28 gm. 10 mm. of4-imino-5,6-dihydro-5-methyl-s-triazine-2-(1H,3H)-one is added 50 ml. ofpyridine, followed by 10 ml. of acetyl chloride at 25° C. for 18 hours.The reaction mixture is evaporated to dryness and is the desired4-imino-N-acetyl-3,4,5,6-tetrahydro-5-methyl-5-triazine-2-(1H)-isisolated by crystallization from methanol.

Preparation 6 Synthesis of precursor,2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride

A reaction mixture consisting of 20 gm. (0.15 mole) 2-deoxy-D-ribose,360 ml. methanol, and 20.0 ml. of a 1% solution of hydrogen chloride inmethanol is stirred for one hour at 25° C. Pyridine is added to a slightexcess, and the volatile components are then removed by evaporationunder reduced pressure. The residue is dissolved in pyridine and thepyridine is evaporated under vacuum. The residue is dissolved in 125 ml.pyridine and the solution is cooled to 0° C. While maintaining thetemperature at 0° C. to 10° C., 50.0 gm. (0.33 mole) p-toluoyl chlorideis added. Afterwards, the reaction mixture is allowed to gradually warmto 25° C. while stirring is continued for about 16 hours. After thisprolonged interval of stirring, the reaction mixture is again cooled to0° C. and 400 ml. water is added followed by 200 ml. chloroform. Theaddition of the water decomposed the excess p-toluoyl chloride. Duringaddition the temperature is not permitted to rise above 10° C. Themixture is stirred for one hour, the organic and aqueous phases areallowed to separate, and the aqueous phase is recovered for purposes ofextration with two-150 ml. portions of chloroform. The combined originalchloroform layer and chloroform extracts is washed with three-100 ml.portions of 3 N sulfuric acid at 5° C., three-100 ml. portions ofsaturated aqueous sodium bicarbonate, and one 200 ml. portion of water.The washed chloroform solution is dried with anhydrous magnesiumsulfate, and after removing the magnesium sulfate by filtration, thechloroform is removed by evaporation under reduced pressure. There isthus obtained 59.5 gm. of 1-methoxy-3,5-di-O-toluoyl-2-deoxy-D-ribose asa dark amber gum. To 73.5 gm. of1-methoxy-3,5-di-O-toluoyl-2-deoxy-D-ribose is added 175 ml. diethylether and this ether solution is poured into 365 ml. of glacial aceticacid that has been saturated at 17° C. with anhydrous hydrogen chloridegas. The addition is optimally made at 0° C. to 5° C. With vigorousstirring at 0° C., additional hydrogen chloride gas is introduced untilcrystals form. Stirring is continued for 3 to 5 minutes beforefiltering. The filter cake is washed thoroughly with diethyl ether, andthe washed crystals are dried under reduced pressure at 25° C. There isthus obtained 48 gm. (66% yield) of1-chloro-3,5-di-O-toluoyl-2-deoxy-D-ribose.

The crude title compound is purified by dissolving the above product inboiling carbon tetrachloride, chilling the solution immediately to minus(-) 10° C. and then setting it aside at 5° C. to 10° C. for 2 hours. Thecrystals of 1-chloro-3,5-di-O-toluoyl-2-deoxy-D-ribose are recovered ona filter.

EXAMPLE 1 Preparation of1-(2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dionePart A: Synthesis of the monosilylated precursor5-ethyl-5,6-dihydro-2-O-(trimethylsilyl)-s-triazine-4-(3H)-one

A reaction mixture consisting of 7.15 gm. (0.05 mole) of5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione prepared in Preparation1, Part C, (above), 150 ml. hexamethyldisilazane, and a catalytic amount(3 mg.) of ammonium sulfate is heated at the reflux temperature for 48hours. The volatiles are removed by evaporation under reduced pressure,and the residue thus obtained is held under reduced pressure for 18hours. The5-ethyl-5,6-dihydro-2-O-(trimethylsilyl)-s-triazine-4-(3H)-one isobtained as a white solid that gave an NMR spectrum in deuteratedchlorform (CDCl₃): NH at 7.9 δ and a ring CH₂ at 4.33 δ (S).

Part B: Preparation of intermediates1-(3,5-di-O-toluoyl-2-deoxy-(β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneand1-(3,5-di-O-toluoyl-2-deoxy-α-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine.

A solution consisting of the 2-O-trimethylsilyl ether of5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione prepared in Part Aabove, and 625 ml. of reagent grade acetonitrile is chilled, in areaction vessel freed of moisture and oxygen by flushing with nitrogen,to a temperature of minus (-) 25° C., before 3.75 ml. of fuming,anhydrous stannic chloride is injected. This reaction mixture is stirredfor five (5) minutes at the minus (-) 25° C. temperature whereupon 10.0gm. (0.025 mole) of 3,5-di-O-toluoyl-2-deoxy-D-ribofuranosyl chloridethat has been dissolved in 20 ml. ethylene dichloride is injected. Thisreaction mixture is stirred at the minus (-) 25° C. for 5 minutes beforetransferring the reaction vessel to a hot water bath where the reactionmixture is warmed to 20° C. Stirring is continued at the 20° C.temperature for 35 minutes when 100 ml. of saturated aqueous sodiumbicarbonate is added. There is then added enough chloroform to bring thetotal volume to 400 ml. The organic phase is recovered and washed oncewith saturated aqueous sodium bicarbonate and once with water. It isdried by adding anhydrous magnesium sulfate. The dried organic solutionis filtered to remove the magnesium sulfate and the filter is rinsedwith 200 ml. chloroform. The chloroform is then removed by evaporationunder reduced pressure to give 10.0 gm. of a foam. The foam is dissolvedin 30 ml. chloroform and the solution is chromatographed over a seriesof three prepacked silica gel columns. (E. Merck, Silica gel 60pre-packed column for liquid chromatography, size C.). The columns aredeveloped with a mixture of cyclohexane and acetone in proportions 2.5to 1. The flow rate is 2 ml./min. and 20 ml. fractions are collected.The eluate in fractions 135 through 180 is recovered by combining thefractions and removing the solvents by evaporation. The product weighs3.15 gm. An analytical sample is obtained by recrystallization from amixture of acetone and Skellysolve B® (1:1 v/v). The product,1-(3,5-di-O-toluoyl-2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,has a melting point of 166.5° C. to 168° C.

Analysis: Calc'd for C₂₆ H₂₉ N₃ O₄ : C, 63.02; H, 5.90; N, 8.48. Found:C, 62.89; H, 5.88; N, 8.24.

[α]_(D) ²⁵ =-47° (c=0.885 in chloroform).

The eluate in fractions 191 through 246 is similarly recovered bycombining the fractions and removing the solvents by evaporation. Theproduct weighs 2.60 gm. An analytical sample is prepared byrecrystallization from a mixture of acetone and Skellysolve B® (1:1v/v). There is thus obtained pure1-(3,5-di-O-toluoyl-2-deoxy-α-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dionehaving a melting point of 134.5° to 136° C.

Analysis: Calc'd for C₂₆ H₂₉ N₃ O₄ : C, 63.02; H, 5.90; N, 8.48. Found:C, 63.29; H, 5.93; N, 8.37.

[α]_(D) ²⁵ =0° (c=0.8935 in chloroform).

Part C: Preparation of desired compound1-(2-deoxy-β-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4(1H,3H)dione

A reaction mixture is obtained by adding 0.33 ml. of a 25% solution ofsodium methoxide in methanol to a solution consisting of 3.2 gm. (0.065mole) of1-(3,5-di-O-toluoyl-2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione(prepared in Part A, above) and 65 ml. methanol. The mixture was stirredfor 18 hours. A few chips of solid carbon dioxide are added and themethanol is removed by evaporation under reduced pressure. The residuethus obtained is dispersed in a mixture of chloroform and water (20 ml.and 100 ml., respectively) and the aqueous phase is allowed to separateand is recovered. It is washed with four-20 ml. portions of chloroformand filtered. The water is removed from filtrate by evaporation underreduced pressure. The solid thus obtained is recrystallized fromabsolute ethanol to give 1.11 gm. of1-(2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dionehaving a melting point of 161.5° to 162.5° C.

Analysis: Calc'd for C₁₀ H₁₇ N₃ O₅ : C, 46.32; H, 6.61; N, 16.21. Found:C, 46.43; H, 6.74; N, 15.68.

[α]_(D) ²⁵ =-7° (c=0.987 in water).

NMR D₂ O gave H₁ ', 3 line pattern at 6.19δ, and ring CH₂, 4.72δ,singlet.

EXAMPLE 2 Preparation of1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dioneand 3',5'-di-O-toluate thereof. Part A: Activated Precursor2,4-bis(trimethylsilyloxy)-5,6-dihydro-5-methyl-s-triazine

A reaction mixture consisting of 1.3 gm. (0.010 mole)5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione in 25 ml. pyridine and6 ml. of bis-trimethylsilyltrifluoroacetamide containing 1%trimethylsilyl chloride is warmed to 50° C. and stirred for 16 hrs. Themixture is then cooled to 25° C., and the pyridine medium along withother volatile components are removed by evaporation under reducedpressure at 60° C. The residue thus obtained is purified by distillingadded toluene under reduced pressure. The toluene distillation isrepeated, and any traces of toluene are removed by holding the residueunder reduced pressure for 16 hrs. at 25° C. There is thus obtained aquantity (about 80% yield) of2,4-bis-(trimethylsilyloxy)-5,6-dihydro-5-methyl-s-triazine.

Part B: Alternative preparation of activated precursor2,4-bis-(trimethylsilyloxy)-5,6-dihydro-5-methyl-s-triazine

A reaction mixture consisting of 1.9 gm. (0.015 mole) of5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione, 50 ml.hexamethyldisilazane, and 2 mg. ammonium sulfate is heated at the refluxtemperature in an environment free from moisture for 48 hours. Themixture is then cooled to 25° C. and the excess hexamethyldisilazane isremoved by evaporation under reduced pressure. Toluene is added to theresidue thus obtained and anhydrous conditions are maintained byflushing with nitrogen gas. Toluene is removed by distillation. Thistoluene distillation is repeated; and the2,4-bis(trimethylsilyloxy)5,6-dihydro-5-methyl-s-triazine thus obtainedis kept under high vacuum until used.

Part C: Synthesis of activated precursor2-(trimethylsilyloxy)5,6-dihydro-5-methyl-s-triazine-4-(3H)-one

A reaction mixture consisting of 1.28 gm. (0.010 mole)5,6-dihydro-5-methyl-s-triazine-2,4(1H,3H)-dione, 40 ml. pyridine, and4.0 ml. bis-trimethylsilyltrifluoroacetamide is stirred continuously at25° C. for 18 hours. The volatiles are then removed by evaporation underreduced pressure, and the residue thus obtained is freed of any pyridineby adding acetonitrile and distilling under reduced pressure. Thedistillation is repeated and there is thus obtained a quantitative yieldof 2-(trimethylsilyoxy)-5,6-dihydro-5-methyl-s-triazine-4(3H)-one.

Part D: Preparation of intermediate1-(2-deoxy-3,5-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione

A solution consisting of 13.6 gm. (0.05 mole) of the activated precursor2,4-bis(trimethylsilyloxy)-5,6-dihydro-5-methyl-s-triazine prepared inPart A, above, and 625 ml. acetonitrile is chilled to minus (-) 24° C.and 3.75 ml. of fuming anhydrous stannic chloride is added. Thissolution is stirred for five (5) minutes, in order to effect solution ofthe catalyst, before a room temperature (28° C.) solution consisting of9.7 gm. (0.025 mole) of 2-deoxy-3,5-ditoluoyl-β-D-ribofuranosyl chlorideand 100 ml. ethylene dichloride is added. This reaction mixture isstirred at minus (-) 20° C. for five (5) minutes before being warmed to25° C. Stirring is continued as the solution gradually becomes a darkgreen color. After adding 100 ml. of saturated aqueous sodiumbicarbonate, the mixture is stirred for one (1) hour, and chloroform isadded until an aqueous phase begins to separate. The aqueous phase isallowed to separate, and the organic phase is recovered. The organicphase is washed once with saturated aqueous sodium bicarbonate and oncewith water. All traces of moisture are removed by drying over anhydrousmagnesium sulfate. The dried solution is filtered, and the magnesiumsulfate on the filter is washed well with chloroform. The filtrate andwashings are combined and the organic solvents are removed byevaporation under reduced pressure followed by high vacuum. The foamyresidue is dissolved in 50 ml. ethyl acetate, and, after seeding, is setaside at 5° C. for 48 hours. The crystallizing mixture is shakenperiodically during the 48 hours. The crystals are collected on afilter, washed well with ethyl acetate, and dried overnight underreduced pressure. There is thus obtained 3.46 gm. (28.8% yield) of thedesired product. A pure sample is prepared by dissolving 2.0 gm. in 45ml. hot ethyl acetate, filtering, concentrating the filtrate toone-third (1/3) its original volume, and crystallizing finally at minus(-) 20° C. There is thus obtained 1.6 gm. (80% yield) of1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dionehaving a melting point of 184° C. to 185° C.

Analysis: Calc'd for C₂₅ H₂₇ N₃ O₉ : C, 62.36; H, 5.65; N, 8.73. Found:C, 62.18; H, 5.69; N, 8.68.

U.V. λ end absorption, 241, 269, 281 nm (ε=31,800, 2,250, 1,300)ethanol.

I.R. NH: 3200 cm⁻¹ ; NH/CH: 3080; C═O: 1730, 1710; C═C/βNH: 1610, 1575,1520; C--C/C--N: 1275, 1265, 1250, 1180, 1110, 1100; other: 755.

[α]_(D) -46° (c=1.087 in chloroform).

NMR: J_(1'-2') α=9 Hz; J_(1'-2') =6 Hz.

Part E: Preparation of1-(2-deoxy-3,5-di-O-toluoyl-(β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dionefrom monosilyloxy precursor,2-(trimethylsilyloxy)-5,6-dihydro-5-methyl-s-triazine-4-(3H)-one

Following the procedure described in Part C, above, but doubling theamounts of reactants and reagents and substituting the2-(trimethylsilyloxy)-5,6-dihydro-5-methyl-s-triazine-4-(3H)-one for2,4-bis(trimethylsilyloxy)-5,6-dihydro-5-methyl-s-triazine there isprepared the corresponding desired intermediate1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dioneweighing 3.8 gm. and having a melting point of 183° C. to 185° C.

Part F: Deacylation to obtain the object compound1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione

To a solution consisting of 7.85 gm. (0.016 mole) of1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione(prepared in Parts C and D, above), and 160 ml. methanol, is added 0.8ml. of a 25% solution of sodium methoxide in methanol. This reactionmixture is stirred for 18 hours when a few chips of solid carbon dioxideare added and stirring is continued for another 10 minutes. Forty gm. ofsilica gel are added and the methanol is removed by evaporation underreduced pressure. The residual white powder thus obtained is transferredto a column of silica gel and then the column is developed with asolution of 5% methanol in chloroform and fractions having positive H₂SO₄ char are combined. After removing the solvents by evaporation, a 1gm. sample of the solid residue is dissolved in 4 ml. of hot methanol towhich solution is added 24 ml. ethyl acetate. Crystallization occurs at25° C., and there is thus obtained 0.79 gm. (79% recovery) of thecompound having a melting point at 142° C. to 143° C.

Analysis: Calc'd for C₉ H₁₅ N₃ O₅ : C, 44.08; H, 6.17; N, 17.13. Found:C, 43.88; H, 6.18; N, 17.31.

Specific Rotation [α]_(D) ²⁵ =-6° (c=0.9168, water).

EXAMPLE 3 Preparation of1-(2-deoxy-β-D-ribofuranosyl)-5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneand the di-O-toluate thereof Part A: Synthesis of the activated,monosilylated precursor5-n-butyl-5,6-dihydro-2-O-(trimethylsilyl)-s-triazine-4-(3H)-one

A reaction mixture consisting of 860 mg. (0.005 mole) of5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione (prepared inPreparation 3, above), 10 ml. pyridine, and 2.5 ml. ofbistrimethylsilyltrifluoro-acetamide containing 1%trimethylsilylchloride are warmed to 50° C. and stirred for 18 hours.The mixture is then cooled to 25° C. and the volatile components areremoved by evaporation under reduced pressure. The residue thus obtainedis dispersed in toluene and the toluene is removed by distillation. Thisprocedure is repeated three times. The residual solid thus obtained isstored under high vacuum until used. The NMR_(CDCl).sbsb.3 is consistentwith monosilylation.

Part B: Preparation of intermediate,1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione

A quantity (12.17 g., 0.005 mole) of5-n-butyl-5,6-dihydro-2-O-(trimethylsilyl)-s-triazine-4-(3H)-one isdispersed in 625 ml. acetonitrile and chilled to minus (-) 22° C. in areaction vessel from which moisture and oxygen has been removed byflushing with nitrogen. To this chilled solution is added (by injection)3.75 ml. of fuming, anhydrous stannic chloride. Stirring is continuedfor 10 minutes, and the reaction mixture becomes homogeneous. There isthen added 9.8 gm. (0.025 mole) of the1-(2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl)-chloride that has beendissolved in 100 ml. ethylene dichloride. After continued stirring atminus (-) 22° C. for 15 minutes, the reaction mixture is warmed to 22°C. in a hot water bath. The reaction mixture is held at 22° C. for 6.5hours when 100 ml. saturated, aqueous sodium bicarbonate is added andthe buffered solution is stirred for 30 minutes. Chloroform is thenadded in an amount sufficient to cause separation of the aqueous phase.The organic phase is removed and washed with 200 ml. water. The washedorganic phase is dried over anhydrous sodium sulfate and the solventsare removed by evaporation under reduced pressure. The semi-solidresidue thus obtained is triturated with 75 ml. hot ethyl acetate andcooled to 25° C. The precipitate that forms weighs 3.6 gm. and it isshown to be starting material. The ethyl acetate filtrate is taken todryness by evaporation and 15 gm. of semi-solid material is transferredto a 650 gm. column of silica gel. The column is developed with 4%methanol in chloroform and the fractions containing nucleoside eluatesare saved and combined. The solvents are removed by evaporation underreduced pressure and the residue thus obtained is dissolved in 30 ml.acetone. Skellysolve B® is added to the acetone solution until trubiditydeveloped. Crystallization proceeded while the turbid mixture is held at25° C. for 18 hours. There is thus obtained 4.9 gm. of white crystals intwo crops. A portion of these crystals (4.1 gm.) is transferred to aseries of three silica gel 60 columns [E. Merck prepacked columns typeC] for medium pressure liquid chromatography with a solvent system ofacetone and cyclohexane in proportions 1:2. The flow rate is 3 ml. perminute and 15 ml. fractions are collected. Fractions 124 through 152 arecombined and the solvents are removed by evaporation under reducedpressure. The residue thus obtained is recrystallized from a mixture ofacetone and Skellysolve B® to give the desired1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,having a melting point of 170.5° to 172° C.

Analysis: Calc'd for C₂₈ H₃₃ N₃ O₇ : C, 64.23; H, 6.35; N, 8.03. Found:C, 64.33; N, 6.28; N, 7.91.

[α]_(D) ²⁵ =-47° (c=0.995 in chloroform).

IR: NH: 3200 cm⁻¹ ; NH/═CH: 3060; C═O: 1725, 1710, 1695; C═C/other:1610, 1575, 1510, 1490; C--O/C--N: 1280, 1250, 1175, 1100, 1085, 1025;other: 755.

Part C: Preparation of the object compound1-(2-deoxy-β-D-ribofuranosyl)-5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione

A reaction mixture consisting of 1.5 gm. (0.0287 mole) of1-(3,5-di-O-toluoyl-2-deoxy-β-D-ribofuranosyl)-5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione(prepared in Part B, above), 70 ml. methanol, and 0.4 ml. of a solutionof 25% sodium methoxide in methanol is stirred for 18 hours at 22° C.Thin-layer chromatography (25% methanol in chloroform) indicates onespot with a Rf 0.7. At this time solid carbon dioxide chips are addeduntil the pH of the solution is 7.0. The methanol is removed byevaporation under reduced pressure. The residue thus obtained isdispersed in a mixture consisting of 50 ml. chloroform and 100 ml.water. The aqueous phase is washed five times with chloroform. Thelayers are separated, and the water is evaporated under reduced pressureat 40° C. There is obtained 0.97 gm. of residue. The residue is placedon a prepacked E. Merck Silica-gel-60 Column, Type C. The column isdeveloped with a solvent mixture consisting of 10 percent methanol inchloroform at the rate of 3 ml. per minute. Fractions containing desiredmaterial, i.e. those fractions indicating positive char with a 50%aqueous sulfuric acid spray, are collected and the solvent mixture isremoved by evaporation under reduced pressure. There is thus obtained0.632 gm. (76.7 percent yield) of preparation of1-(2-deoxy-β-D-ribofuranosyl)-5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneas a clear glass.

Analysis: Calc'd for C₁₂ H₂₁ N₂ O₅ : C, 50.16; H, 7.37; N, 14.62. Found:C, 49.71; H, 7.17; N, 14.38.

EXAMPLE 4 Part A

Following the procedure described in Example 1, Part A, but substitutingfor the 5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione

3,4,5,6-tetrahydro-4-imino-s-triazine-2-(1H)-one,

3,4,5,6-tetrahydro-4-imino-5-methyl-s-traizine-2-(1H)-one,

3,4,5,6-tetrahydro-4-imino-5-ethyl-s-triazine-2-(1H)-one,

3,4,5,6-tetrahydro-4-imino-5-n-propyl-s-triazine-2-(1H)-one,

3,4,5,6-tetrahydro-4-imino-5-cyclopropyl-s-triazine-2-(1H)-one,

3,4,5,6-tetrahydro-4-imino-5-isopropyl-s-triazine-2-(1H)-one,

4-(acetylimino)-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

4-(acetylamino)-3,4,5,6-tetrahydro-5-methyl-s-triazine-2-(1H)-one,

4-(acetylimino)-3,4,5,6-tetrahydro-5-ethyl-s-triazine-2-(1H)-one,

4-(acetylimino)-3,4,5,6-tetrahydro-5-n-propyl-s-triazine-2-(1H)-one,

4-(acetylimino)-3,4,5,6-tetrahydro-5-cyclopropyl-s-triazine-2-(1H)-one,

4-(acetylimino)-3,4,5,6-tetrahydro-5-isopropyl-s-triazine-2-(1H)-one,

5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

6-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

5-cyclopropyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

5-n-propyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

5-isopropyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

5-methoxymethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

5-methylthiomethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

5-methyl-5,6-dihydro-2-thio-s-triazine-4-(1H,3H)-one,

5-ethyl-5,6-dihydro-2-thio-s-triazine-4-(1H,3H)-one, there are preparedthe corresponding:

3,4,5,6-tetrahydro-4-imino-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-methyl-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-ethyl-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-n-propyl-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-cyclopropyl-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-isopropyl-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-5-methyl-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-5-ethyl-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-5-n-propyl-2-O-trimethylsilyl-s-triazine

4-(acetylimino)-3,4,5,6-tetrahydro-5-cyclopropyl-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-5-isopropyl-2-O-trimethylsilyl-s-triazine,

5,6,-dihydro-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-6-methyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-cyclopropyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-n-propyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-isopropyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-methoxymethyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-methylthiomethyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-methyl-2-thio-trimethylsilyl-s-triazine-4-(3H)-one, and

5,6-dihydro-5-ethyl-2-thio-trimethylsilyl-s-triazine-4-(3H)-onerespectively.

Part B

Following the procedure described in Example 1, Part B, but substituting

3,4,5,6-tetrahydro-4-imino-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-methyl-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-ethyl-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-n-propyl-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-cyclopropyl-2-O-trimethylsilyl-s-triazine,

3,4,5,6-tetrahydro-4-imino-5-isopropyl-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-5-methyl-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-5-ethyl-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-5-n-propyl-2-O-trimethylsilyl-s-triazine

4-(acetylimino)-3,4,5,6-tetrahydro-5-cyclopropyl-2-O-trimethylsilyl-s-triazine,

4-(acetylimino)-3,4,5,6-tetrahydro-5-isopropyl-2-O-trimethylsilyl-s-triazine,

5,6-dihydro-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6,-dihydro-6-methyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-cyclopropyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-n-propyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-isopropyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-methoxymethyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-methylthiomethyl-2-O-trimethylsilyl-s-triazine-4-(3H)-one,

5,6-dihydro-5-methyl-2-thio-trimethylsilyl-s-triazine-4-(3H)-one, and

5,6-dihydro-5-ethyl-2-thio-trimethylsilyl-s-triazine-4-(3H)-onerespectively, for the5-ethyl-5,6-dihydro-2-O-(trimethylsilyl)-s-triazine-4-(3H)-one, thereare prepared the corresponding:

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-methyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-ethyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-n-propyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-cyclopropyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-isopropyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-methyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-ethyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-n-propyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-cyclopropyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-isopropyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-6-methyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-cyclopropyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-n-propyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-isopropyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-methoxymethyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-methylthiomethyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-2-thio-s-triazine-4-(1H,3H)-one,and

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-ethyl-2-thio-s-triazine-4-(1H,3H)-one,respectively.

Part C

Following the procedure described in Example 1, Part C, but substituting

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-methyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-ethyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-n-propyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-cyclopropyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-5-isopropyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-methyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-ethyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-n-propyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-cyclopropyl-s-triazine-2-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-4-(acetylimino)-3,4,5,6-tetrahydro-5-isopropyl-s-(1H)-one,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-6-methyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-cyclopropyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-n-propyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-isopropyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-methoxymethyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-methylthiomethyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-2-thio-s-triazine-4-(1H,3H)-one,and

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5,6-dihydro-5-ethyl-2-thio-s-triazine-4-(1H,3H)-one,for the1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranoyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,there are prepared the corresponding:

1-(2-deoxy-β-D-ribofuranosyl)-4-imino-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

1-(2-deoxy-β-D-ribofuranosyl)-4-imino-5-methyl-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

1-(2-deoxy-β-D-ribofuranosyl)-4-imino-5-ethyl-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

1-(2-deoxy-β-D-ribofuranosyl)-4-imino-5-n-propyl-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

1-(2-deoxy-β-ribofuranosyl)-4-imino-5-cyclopropyl-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

1-(2-deoxy-β-D-ribofuranosyl)-4-imino-5-isopropyl-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,

1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione

1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-6-methyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-cyclopropyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-n-propyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-isopropyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methoxymethyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methylthio-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-2-thio-s-triazine-4-(1H,3H)-one,and

1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-ethyl-2-thio-s-triazine-4-(1H,3H)-one.

EXAMPLE 5

Following the procedure described in Example 1, Part B, but substituting

1-(2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl)-chloride,

1-(2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl)-bromide,

1-(2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl)-chloride,

1-(2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl)-chloride,

1-(2-deoxy-3,5-di-O-chlorobenzoyl-D-ribofuranosyl)-chloride,

1-(2-deoxy-3,5-di-O-toluoyl-D-xylofuraosyl)-chloride for the1-(2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl)-chloride, there areprepared the corresponding:

1-(2-deoxy-3,5-di-O-acetyl-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-benzoyl-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-p-nitrobenzoyl-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-3,5-di-O-p-chlorobenzoyl-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,and

1-(2-deoxy-3,5-di-O-toluoyl-β-D-xylofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,respectively.

The1-(2-deoxy-β-D-pentofuranosyl)-5,6-dihydro-4-imino-s-triazine-2-(1H,3H)-onesand thiones of this invention (compounds according to Formula Ia whereinX is imino) form acid addition salts with acids, for example,hydrochloric, sulfuric, phosphoric, benzoic, acetic, propionic, picric,citric, succinic, maleic, tartaric, thiocyanuric, and fluosilicic acid.Such acid addition salts are useful for purifying the free basecompounds and for metathetic reactions to form still other acid additionsalts. The acid addition salts have sometimes advantageous solubilityproperties over the free bases.

EXAMPLE 6 Preparation of1-(2-deoxy-3-lauroyl-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dionePart A:1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione

A reaction mixture consisting of 12.25 gm. (0.050 mole) of1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione,50 ml. dimethylformamide, and 8.5 gm. (0.125 mole) of imidazole waswarmed to 35° C. and stirred until the imidazole had dissolved. Therewas then added with continued stirring 7.55 gm. (0.050 mole)tert-butyldimethylsilyl chloride. Stirring was continued for 18 hours at35° C. The solvent medium was then removed by evaporation under reducedpressure, and the residue thus obtained was dispersed in a solventmixture consisting of 200 ml. chloroform and 50 ml. water. The twophases were allowed to stabilize and the aqueous phase was recovered. Itwas washed two times with 50 ml. portions of chloroform. The threechloroform layers (original and two washes) were combined and washedwith three-25 ml. portions of water. The washed chloroform solution wasdried over anhydrous magnesium sulfate and filtered. The chloroform wasthen removed by evaporation under reduced pressure to give 14.8 gm.(82.5% yield) of1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione.

Part B: 1-(5-tertbutyldimethylsilyl-3-lauroyl-2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione

To a solution consisting of 3.59 gm. (0.010 mole) of1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dioneand 30 ml. A.R. pyridine that had been cooled to 5° C. was added, withstirring, 2.55 gm. (0.0116 mole) of freshly distilled lauroyl chloride.This reaction mixture was stirred for 18 hours at 25° C. Then it wascooled to 10° C. and 3 ml. water was added. This mixture was stirred at25° C. while the solvents were removed by evaporation under reducedpressure. The residue thus obtained was dispersed in a solvent mixtureconsisting of 100 ml. chloroform and 50 ml. saturated aqueous sodiumbicarbonate. The aqueous and organic phases were allowed to stabilizeand the organic phase was saved. It was washed two times with 50 ml.portions of saturated aqueous sodium bicarbonate and dried overanhydrous magnesium sulfate. The dried chloroform solution was filteredand the filter was washed with chloroform. The filtrate and washingswere combined and the chloroform was removed by evaporation underreduced pressure. There was thus obtained 4.8 gm. (88.7% yield) of1-(5-tert-butyldimethylsilyl-3-lauroyl-2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione.

Following the same procedure, but substituting1-(2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-β-D-ribofuranosyl)-5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-β-D-ribofuranosyl)-5-n-propyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-β-D-ribofuranosyl)-5-cyclopropyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,and

1-(2-deoxy-β-D-ribofuranosyl)-3,4,5,6-tetrahydro-4-imino-5-methyl-s-triazine-2-(1H)-onefor the1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dionethere are prepared the corresponding:

1-(2-deoxy-5-lauroyl-β-D-ribofuranosyl)-5ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-5-lauroyl-β-D-ribofuranosyl)-5-n-butyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-5-lauroyl-β-D-ribofuranosyl)-5,6-dihydro-5-n-propyl-s-triazine-2,4-(1H,3H)-dione,

1-(2-deoxy-5-lauroyl-β-D-ribofuranosyl)-5-cyclopropyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,and

1-(2-deoxy-5-lauroyl-β-D-ribofuranosyl)-4-imino-5-methyl-3,4,5,6-tetrahydro-s-triazine-2-(1H)-one,respectively.

Part C: Object compound1-(2-deoxy-3-lauroyl-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione

A reaction mixture consisting of 4.8 gm. (0.009 mole) of2-(5-tert-butyldimethylsilyl-3-lauroyl-2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione,26 ml. tetrahydrofuran and 28 ml. tetra-n-butyl ammonium floride intetrahydrofuran was allowed to stand for 18 hours at 25° C. The mediumwas then removed by evaporation under reduced pressure, and the residuethus obtained was dissolved in 200 ml. chloroform. The chloroformsolution was washed with two-50 ml. portions of saturated aqueous sodiumbicarbonate and three-50 ml. portions water, and then dried overanhydrous magnesium sulfate. The washed chloroform solution was filteredand the residue was washed with additional chloroform which was added tothe filtrate. The chloroform was then removed by evaporation underreduced pressure to give a semisolid residue. This residue was dissolvedin 25 ml. acetone and technical hexane was added to the acetone solutionuntil it became cloudy. After seeding, the cloudy solution was allowedto crystallize for 18 hours at 25° C. The crystals were collected on afilter and washed with a mixture of acetone and technical hexane. Therewas thus obtained 1.41 gm. of1-(2-deoxy-3-lauroyl-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione.An analytical sample was prepared by recrystallizing 1.4 gm. from amixture of 20 ml. acetone and 25 ml. hexane. It weighed 1.15 gm. and hada melting point at 136° C. to 137° C.

Analysis: Calc'd for C₂₁ H₃₇ N₃ O₆ : C, 58.99; H, 8.72; N, 9.82. Found:C, 58.83; H, 8.98; N, 9.43.

IR: OH: 3480 cm⁻¹ ; NH: 3200, 3080; C═O: 1740, 1710, 1695, and 1685;BNH/Other: 1520; C-O/C-N: 1270, 1165, 1105; Other: 725.

The following is a comparative test of1-(2-deoxy-β-D-ribofuranosyl)-5-ethyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,U-50,365 and1-(2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione,U-44,590. Mean survival time (MST) in days and per ant survivors (% s)is given. The compounds are administered subcutaneously to mice whichare inoculated intravenously with 3×10⁵ PFM (MRS) Herpes simplex virus(HSV-1). Treatment is initiated one hour after virus inoculation and isfollowed by treatment three times daily for five consecutive days. Adetailed account of the materials, methods and results are as follows.

Male mice, weighing approximately 18 gm. each, are divided into eightgroups of 20. Group 1 is treated with Sterile saline, group 2 with 400mg./kg./dose (mkd) U-44,590, group 3 with 200 mkd U-44,590, group 4 with100 mkd U-44,590, group 5 with 50 mkd U-44,590, group 6 with 200 mkdU-50,365, group 7 with 100 mkd U-50,365, and group B with 50 mkdU-50,365. The test compound is dissolved in Sterile saline andadministered subcutaneously in the nape of the neck at 8:00 a.m., 12:00noon, and 4:00 p.m. on days 1, 2, 3 and 4. 3×10⁵ PFU (MRS) herpessimplex virus (HSV-1) is inoculated into the tail vein at 8:00 a.m. onday 0. On day 0, the test compound is given at 9:00 a.m., 12:00 noon,and 4:00 p.m. Death and paralysis are recorded daily.

Hind leg paralysis usually preceeded death by 1-2 days. All mice diedthat became paralyzed. Death pattern of the 8 groups, as shown in thecurves of FIG. 1, illustrates the dose response obtained.

In addition to its antiviral activity, U-50,365 is less cytotoxic thanU-44,590 and as determined by Standard microbiological disk plate assaysdid not exhibit antibacterial activity against Bacillus subtillis,Staphylococcus aureus, Sarcina lutea, Klebsiella pneumoniae, Escherichiacoli, Salmonella schottmulleri, Proteus vulgaris, Mycobacterium avium,Penicillium oxalicum, Saccharomyces pastorianus Pseudomonas aeruginosaor Pseudomonas fluorescens with assay disks treated with 20 microlitersof a 1 mg./ml. aqueous solution of U-50,365.

I claim:
 1. The chemical process which comprises reacting a monosilylcompound of the formula: ##STR11## wherein R is selected from the groupconsisting of hydrogen, lower alkyl of 1 through 4 carbon atoms, andcyclopropyl and R' is selected from the group consisting of hydrogen andlower alkyl of 1 through 4 carbon atoms; with a2-deoxy-3,5-blocked-D-pentofuranosyl halide in the presence of a Lewisacid and a solvent selected from the group consisting of acetonitrile ornitromethane at a temperature of about minus (-) 25° C. with subsequentwarming to about 25° C.; to form a1-(2-deoxy-3,5-di-O-blocked-D-pentofuranosyl)-5-R-6-R'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.2. The process according to claim 1, wherein the monosilyl compound isreacted with a 2-deoxy-3,5-blocked-D-pentofuranosyl chloride in thepresence of stannic chloride.
 3. The process according to claim 2,wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is a2-deoxy-3,5-blocked-D-ribofuranosyl chloride.
 4. The process accordingto claim 3, wherein the monosilyl compound is5-ethyl-5,6-dihydro-2-O-trimethylsilyl-s-triazine-4-(3H)-one.
 5. Theprocess according to claim 4, wherein the2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the groupconsisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.
 6. The processaccording to claim 3 wherein the monosilyl compound is5-methyl-5,6-dihydro-2-O-trimethyl-silyl-4-(3H)-one.
 7. The processaccording to claim 6, wherein the 2-deoxy-3,5-blocked-D-ribofuranosylchloride is selected from the group consisting of2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.
 8. Thechemical process which comprises reacting a 2,4-bis-silyl compound ofthe formula: ##STR12## wherein R is selected from the group consistingof hydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyland R' is selected from the group consisting of hydrogen and lower alkylof 1 through 4 carbon atoms; with a 2-deoxy-3,5-blocked-D-pentofuranosylhalide in the presence of a Lewis acid and a solvent selected from thegroup consisting of acetonitrile or nitromethane at a temperature ofabout minus (-) 25° C. with subsequent warming to about 25° C.; to forma1-(2-deoxy-3,5-di-O-blocked-β-D-pentofuranosyl)-5-R-6-R'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.9. The process according to claim 8, wherein the bis-silyl compound isreacted with a 2-deoxy-3,5-di-blocked-D-pentofuranosyl chloride in thepresence of stannic chloride.
 10. The process according to claim 9,wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is a2-deoxy-3,5-blocked-D-ribofuranosyl chloride.
 11. The process accordingto claim 10, wherein the bis-silyl compound is5-ethyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine.
 12. The processaccording to claim 11, wherein the 2-deoxy-3,5-blocked-D-ribofuranosylchloride is selected from the group consisting of2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, and a2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.
 13. Theprocess according to claim 10, wherein the bis-silyl compound is5-methyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine.
 14. Theprocess according to claim 13, wherein the2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the groupconsisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, and a2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride.
 15. The chemicalprocess which comprises reacting a monosilyl compound of the formula:##STR13## wherein R is selected from the group consisting of hydrogen,lower alkyl of 1 through 4 carbon atoms, and cyclopropyl and R' isselected from the group consisting of hydrogen and lower alkyl of 1through 4 carbon atoms; with a 2-deoxy-3,5-blocked-D-pentofuranosylhalide in the presence of a Lewis acid and acetonitrile at a temperatureof about minus (-) 25° C. with subsequent warming to about 25° C.; toform a1-(2-deoxy-3,5-di-O-blocked-β-D-pentofuranosyl)-5-R-6-R'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.16. The process according to claim 15, wherein the monosilyl compound isreacted with a 2-deoxy-3,5-blocked-D-pentofuranosyl chloride in thepresence of stannic chloride.
 17. The process according to claim 16,wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is a2-deoxy-3,5-blocked-D-ribofuranosyl chloride.
 18. The process accordingto claim 17, wherein the monosilyl compound is5-ethyl-5,6-dihydro-2-O-trimethylsilyl-s-triazine-4-(3H)-one.
 19. Theprocess according to claim 18, wherein the2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the groupconsisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.
 20. Theprocess according to claim 17 wherein the monosilyl compound is5-methyl-5,6-dihydro-2-O-trimethyl-silyl-4-(3H)-one.
 21. The processaccording to claim 20, wherein the 2-deoxy-3,5-blocked-D-ribofuranosylchloride is selected from the group consisting of2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.
 22. Thechemical process which comprises reacting a 2,4-bis-silyl compound ofthe formula: ##STR14## wherein R is selected from the group consistingof hydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyland R' is selected from the group consisting of hydrogen and lower alkylof 1 through 4 carbon atoms; with a 2-deoxy-3,5-blocked-D-pentofuranosylhalide in the presence of a Lewis acid and acetonitrile at a temperatureof about minus (-) 25° C. with subsequent warming to about 25° C.; toform a1-(2-deoxy-3,5-di-O-blocked-β-D-pentofuranosyl)-5-R-6-R'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.23. The process according to claim 22, wherein the bis-silyl compound isreacted with a 2-deoxy-3,5-di-blocked-D-pentofuranosyl chloride in thepresence of stannic chloride.
 24. The process according to claim 23,wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is a2-deoxy-3,5-blocked-D-ribofuranosyl chloride.
 25. The process accordingto claim 24, wherein the bis-silyl compound is5-ethyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine.
 26. The processaccording to claim 25, wherein the 2-deoxy-3,5-blocked-D-ribofuranosylchloride is selected from the group consisting of2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.
 27. Theprocess according to claim 24, wherein the bis-silyl compound is5-methyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine.
 28. Theprocess according to claim 27, wherein the2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the groupconsisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, and a2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride.
 29. The chemicalprocess which comprises reacting a monosilyl compound of the formula:##STR15## wherein R is selected from the group consisting of hydrogen,lower alkyl of 1 through 4 carbon atoms, and cyclopropyl and R' isselected from the group consisting of hydrogen and lower alkyl of 1through 4 carbon atoms; with a 2-deoxy-3,5-blocked-D-pentofuranosylhalide that has been dissolved in ethylene dichloride, in the presenceof stannic chloride and acetonitrile at a temperature of about minus (-)25° C. with subsequent warming to about 25° C.; to form a1-(2-deoxy-3,5-di-O-blocked-β-D-pentofuranosyl)-5-R-6-R'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.30. The process according to claim 29, wherein the2-deoxy-3,5-blocked-D-pentofuranosyl chloride is2-deoxy-3,5-blocked-D-ribofuranosyl chloride.
 31. The process accordingto claim 30, wherein the monosilyl compound is selected from the groupconsisting of5-ethyl-5,6-dihydro-2-O-trimethylsilyl-s-triazine-4-(3H)-one or5-methyl-5,6-dihydro-2-O-trimethylsilyl-4-(3H)-one.
 32. The chemicalprocess which comprises reacting a 2,4-bis-silyl compound of theformula: ##STR16## wherein R is selected from the group consisting ofhydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyl andR' is selected from the group consisting of hydrogen and lower alkyl of1 through 4 carbon atoms; with a 2-deoxy-3,5-blocked-D-pentofuranosylhalide that has been dissolved in ethylene dichloride, in the presenceof stannic chloride and acetonitrile at a temperature of about minus (-)25° C. with subsequent warming to about 25° C.; to form a1-(2-deoxy-3,5-di-O-blocked-β-D-pentofuranosyl)-5-R-6-R'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.33. The process according to claim 32, wherein the2-deoxy-3,5-blocked-D-pentofuranosyl chloride is2-deoxy-3,5-blocked-D-ribofuranosyl chloride.
 34. The process accordingto claim 33, wherein the bis-silyl compound is selected from the groupconsisting of5-ethyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine-4-(3H)-one or5-methyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-4-(3H)-one.